de Souza Fernandez T, Menezes de Souza J, Macedo Silva M L, Tabak D, Abdelhay E
Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Brazil.
Leuk Res. 1998 Feb;22(2):125-34. doi: 10.1016/s0145-2126(97)00112-4.
A cytogenetic and N-ras point mutation study was done in patients with primary myelodysplastic syndrome (MDS) from Rio de Janeiro, Brazil, in order to evaluate the progression of preleukemic states to overt leukemia. Cytogenetic analysis was performed in 50 patients with MDS and clonal chromosomal abnormalities were detected in 19 (38%) of them. Patients with refractory anemia (RA) or with ringed sideroblasts (RARS) presented normal karyotypes or single abnormalities as del(5q) or -Y, while patients in more advanced states as RA with excess of blasts (RAEB), RAEB in transformation (RAEB-t) and chronic myelomonocytic leukemia (CMML) showed complex karyotypes and single abnormalities involving chromosomes 7 or 8, which were related to poor prognosis and elevated risk of transformation to acute myeloid leukemia (AML). The frequency of ras activation was studied in these 50 patients with MDS. Samples of bone marrow were screened for oncogenic point mutations by DNA amplification followed by oligonucleotide hybridization analysis (PCR-ASO) at codon 12 of N-ras proto-oncogene. We detected N-ras point mutations in 21 patients (42%). Progression from MDS to AML was observed in 9 patients (18%). The correlation analysis between N-ras point mutations and specific chromosomal abnormalities indicated that although mutated N-ras was found in cells with del(5q) and monosomy 7, cells with those abnormalities and normal N-ras were also identified. Otherwise trisomy of chromosome 8 showed a correlation with N-ras point mutations and in all cases, patients showed progression of MDS to AML during the follow-up study. MDS comprises a heterogeneous group of hematopoietic disorders and probably several steps are implicated in the evolution to AML. In this work we suggest that one possible pathway of leukemogenesis in MDS includes N-ras point mutations in association with trisomy of chromosome 8.
为了评估白血病前期状态向明显白血病的进展情况，对来自巴西里约热内卢的原发性骨髓增生异常综合征（MDS）患者进行了细胞遗传学和N-ras点突变研究。对50例MDS患者进行了细胞遗传学分析，其中19例（38%）检测到克隆性染色体异常。难治性贫血（RA）或环形铁粒幼细胞性贫血（RARS）患者表现为正常核型或单一异常，如del(5q)或-Y，而处于更晚期状态的患者，如伴有原始细胞增多的RA（RAEB）、转化中的RAEB（RAEB-t）和慢性粒单核细胞白血病（CMML），则表现为复杂核型和涉及7号或8号染色体的单一异常，这些与预后不良和转化为急性髓系白血病（AML）的风险升高有关。研究了这50例MDS患者中ras激活的频率。通过DNA扩增，随后进行N-ras原癌基因第12密码子的寡核苷酸杂交分析（PCR-ASO），对骨髓样本进行致癌点突变筛查。我们在21例患者（42%）中检测到N-ras点突变。9例患者（18%）观察到从MDS进展为AML。N-ras点突变与特定染色体异常之间的相关性分析表明，虽然在伴有del(5q)和7号染色体单体的细胞中发现了突变的N-ras，但也鉴定出了具有这些异常且N-ras正常的细胞。此外，8号染色体三体与N-ras点突变相关，并且在所有病例中，患者在随访研究期间均表现出从MDS进展为AML。MDS是一组异质性造血疾病，可能有几个步骤参与了向AML的演变。在这项研究中，我们认为MDS白血病发生的一种可能途径包括与8号染色体三体相关的N-ras点突变。
